Barnes Thomas R E, Leeson Verity C, Paton Carol, Costelloe Céire, Simon Judit, Kiss Noemi, Osborn David, Killaspy Helen, Craig Tom K J, Lewis Shôn, Keown Patrick, Ismail Shajahan, Crawford Mike, Baldwin David, Lewis Glyn, Geddes John, Kumar Manoj, Pathak Rudresh, Taylor Simon
Centre for Mental Health, Imperial College London, London, UK.
West London Mental Health NHS Trust, London, UK.
Health Technol Assess. 2016 Apr;20(29):1-46. doi: 10.3310/hta20290.
Negative symptoms of schizophrenia represent deficiencies in emotional responsiveness, motivation, socialisation, speech and movement. When persistent, they are held to account for much of the poor functional outcomes associated with schizophrenia. There are currently no approved pharmacological treatments. While the available evidence suggests that a combination of antipsychotic and antidepressant medication may be effective in treating negative symptoms, it is too limited to allow any firm conclusions.
To establish the clinical effectiveness and cost-effectiveness of augmentation of antipsychotic medication with the antidepressant citalopram for the management of negative symptoms in schizophrenia.
A multicentre, double-blind, individually randomised, placebo-controlled trial with 12-month follow-up.
Adult psychiatric services, treating people with schizophrenia.
Inpatients or outpatients with schizophrenia, on continuing, stable antipsychotic medication, with persistent negative symptoms at a criterion level of severity.
Eligible participants were randomised 1 : 1 to treatment with either placebo (one capsule) or 20 mg of citalopram per day for 48 weeks, with the clinical option at 4 weeks to increase the daily dosage to 40 mg of citalopram or two placebo capsules for the remainder of the study.
The primary outcomes were quality of life measured at 12 and 48 weeks assessed using the Heinrich's Quality of Life Scale, and negative symptoms at 12 weeks measured on the negative symptom subscale of the Positive and Negative Syndrome Scale.
No therapeutic benefit in terms of improvement in quality of life or negative symptoms was detected for citalopram over 12 weeks or at 48 weeks, but secondary analysis suggested modest improvement in the negative symptom domain, avolition/amotivation, at 12 weeks (mean difference -1.3, 95% confidence interval -2.5 to -0.09). There were no statistically significant differences between the two treatment arms over 48-week follow-up in either the health economics outcomes or costs, and no differences in the frequency or severity of adverse effects, including corrected QT interval prolongation.
The trial under-recruited, partly because cardiac safety concerns about citalopram were raised, with the 62 participants recruited falling well short of the target recruitment of 358. Although this was the largest sample randomised to citalopram in a randomised controlled trial of antidepressant augmentation for negative symptoms of schizophrenia and had the longest follow-up, the power of statistical analysis to detect significant differences between the active and placebo groups was limited.
Although adjunctive citalopram did not improve negative symptoms overall, there was evidence of some positive effect on avolition/amotivation, recognised as a critical barrier to psychosocial rehabilitation and achieving better social and community functional outcomes. Comprehensive assessment of side-effect burden did not identify any serious safety or tolerability issues. The addition of citalopram as a long-term prescribing strategy for the treatment of negative symptoms may merit further investigation in larger studies.
Further studies of the viability of adjunctive antidepressant treatment for negative symptoms in schizophrenia should include appropriate safety monitoring and use rating scales that allow for evaluation of avolition/amotivation as a discrete negative symptom domain. Overcoming the barriers to recruiting an adequate sample size will remain a challenge.
European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2009-009235-30 and Current Controlled Trials ISRCTN42305247.
This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 29. See the NIHR Journals Library website for further project information.
精神分裂症的阴性症状表现为情感反应、动机、社交、言语及运动方面的缺陷。若这些症状持续存在，被认为是导致精神分裂症患者功能预后不良的主要原因。目前尚无获批的药物治疗方法。现有证据表明，抗精神病药物与抗抑郁药物联合使用可能对治疗阴性症状有效，但证据有限，无法得出确切结论。
确定在精神分裂症患者中，使用抗抑郁药物西酞普兰增强抗精神病药物治疗阴性症状的临床疗效及成本效益。
一项多中心、双盲、个体随机、安慰剂对照试验，随访12个月。
成人精神科服务机构，负责治疗精神分裂症患者。
正在接受持续、稳定抗精神病药物治疗且阴性症状达到一定严重程度标准的精神分裂症住院或门诊患者。
符合条件的参与者按1∶1随机分为两组，一组接受安慰剂（一粒胶囊）治疗，另一组每天服用20毫克西酞普兰，为期48周；在4周时，临床医生可选择将西酞普兰每日剂量增加至40毫克或服用两粒安慰剂胶囊，直至研究结束。
主要结局指标为使用海因里希生活质量量表在12周和48周时评估的生活质量，以及在12周时使用阳性和阴性症状量表阴性症状分量表测量的阴性症状。
在12周或48周时，未发现西酞普兰在改善生活质量或阴性症状方面有治疗益处，但二次分析表明，在12周时，阴性症状领域的意志缺乏/动机缺乏有适度改善（平均差值 -1.3，95%置信区间 -2.5至 -0.09）。在48周的随访中，两个治疗组在卫生经济学结局或成本方面均无统计学显著差异，在不良反应的频率或严重程度方面也无差异，包括校正QT间期延长。
该试验招募人数不足，部分原因是对西酞普兰的心脏安全性提出了担忧，招募的62名参与者远低于358名的目标招募人数。尽管这是在抗抑郁药物增强治疗精神分裂症阴性症状的随机对照试验中随机分配至西酞普兰组的最大样本，且随访时间最长，但检测活性组与安慰剂组之间显著差异的统计分析效能有限。
尽管辅助使用西酞普兰并未总体上改善阴性症状，但有证据表明其对意志缺乏/动机缺乏有一定积极作用，而意志缺乏/动机缺乏被认为是心理社会康复及实现更好社会和社区功能结局的关键障碍。对副作用负担的综合评估未发现任何严重的安全性或耐受性问题。将西酞普兰作为治疗阴性症状的长期处方策略可能值得在更大规模的研究中进一步探讨。
关于辅助使用抗抑郁药物治疗精神分裂症阴性症状可行性的进一步研究应包括适当的安全性监测，并使用能够将意志缺乏/动机缺乏作为一个独立的阴性症状领域进行评估的评定量表。克服招募足够样本量的障碍仍将是一项挑战。
欧盟药品监管当局临床试验（EudraCT）编号2009 - 009235 - 30及当前受控试验ISRCTN42305247。
本项目由英国国家卫生研究院卫生技术评估项目资助，将全文发表于《卫生技术评估》；第20卷，第29期。有关进一步的项目信息，请访问英国国家卫生研究院期刊图书馆网站。
